Bupropion hydrochloride is a known antidepressant sold in immediate release and sustained release tablet form under the brand names WELLBUTRIN.RTM. and ZYBAN.RTM.. Bupropion hydrochloride is an antidepressant of the aminoketone class and is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors or other known antidepressant agents. Bupropion (BUP) hydrochloride is highly metabolized in both rats and humans. The major metabolites are the erythroamino alcohol (EB), the threoamino alcohol (TB), and the hydroxy metabolite (HB). The metabolites exhibit pharmacological activity in an antitetrabenzene model. Bupropion hydrochloride is also used in preventing functional impairment and drowsiness seen upon administration of benzodiazepine, in the treatment of minimal brain dysfunction, tardive dyskinesia, impaired mental alertness upon ingestion of ethanol and psychosexual dysfunction and in promoting weight loss. While the immediate release and sustained release tablets currently sold are suitable for the indicated use, there is a disadvantage to bupropion hydrochloride in that there can be an accumulation of metabolites that can be detrimental to one's health.
In a study of pharmacokinetics of bupropion hydrochloride in the elderly, six elderly patients with diagnosed depression were examined in a single and multiple dose study. Half-lives (t1/2app) of the metabolites TB, EB and HB were 38.8+/-7.6 hours, 61.4 +/-21.6 hours and 34.2 +/-4.6 hours, respectively. After multiple dosing, the half-life for bupropion and its metabolites did not change significantly although in some patients the half-life of metabolites was substantially prolonged. In addition, there was also evidence of inordinate accumulation of metabolites. The elderly are at risk for accumulation of bupropion and its metabolites. See J. Clin. Pharmacol. 35:876-884 (1995).
Therefore a need exists for a new form of bupropion for delivery to the body while minimizing the formation of metabolites.
According to WO 99/11208 to Williams et al, an attempt was made to prepare bupropion hydrochloride in the form of a composition to be administered transdermally. According to Examples 5 and 19 of this patent publication, a transdermal system was prepared by grinding tablets of bupropion hydrochloride to a fine powder which was dissolved in purified water, filtered and used to make a 20% pluronic gel. This gel and soya lecithin were mixed with syringes and diluted further with pluronic gel F127 to obtain a total of two 60 c.c. batches of bupropion hydrochloride having a strength of 15 mg/ml.
Furthermore, this gel was applied by each of the 3 patients (self-administered) to the skin for a period of 1 hour. The dosage of 50 to 200 mg/day was made in one example.
The administered gel did not deliver the drug bupropion (or at least enough bupropion) into the systemic circulation as no clinical responses or measurable levels of bupropion were noted after its application to the skin for a period of at least one hour according to Example 31. Williams et al express the conclusion on page 19 that both the laboratory measure and the patient clinical response indicated poor or equivocal absorption and results for transdermally administered bupropion hydrochloride.
According to Williams et al bupropion tablets were ground to dissolve the bupropion in water, filtered and then used in gel formulation. Bupropion tablets marketed worldwide contain (+/-) bupropion hydrochloride which is highly water-soluble. Bupropion hydrochloride is the HCl salt of an aminoketone which is not very stable; therefore it needs to be stabilized in tablet formations. Moreover, as a hydrochloride salt, bupropion HCl cannot be easily transported through the skin. The absorption of bupropion HCl into the systemic circulation requires that the hydrochloride salt be converted to base bupropion which is much more unstable. Even if in the gel matrix made from Pluronic F127 NF and potassium sorbate, bupropion hydrochloride is converted into bupropion base, the question arises as to how this base was stabilized. Bupropion base needs to be stabilized; otherwise the base undergoes decomposition.
U.S. Pat. No. 5,358,970 to Ruff et al discloses bupropion hydrochloride stabilized with a number of acidic stabilizing agents including L-cysteine hydrochloride, glycine hydrochloride, malic acid, sodium metabisulfite, citric acid, tartaric acid, and L-cysteine dihydrochloride. The stabilized bupropion hydrochloride is in the form of a solid pharmaceutical composition that may be employed in tablets or capsules. There is no disclosure or suggestion of stabilizing bupropion base nor is there a disclosure or suggestion of preparing a composition containing any form of bupropion in a composition suitable for transdermal administration.
WO 99/38503 to McCullough et al and WO 99/38502 and 99/38504 to Young each disclose an optically active form of bupropion or bupropion in the form of a pharmaceutically acceptable salt in the treatment of depression or to facilitate the stopping of smoking tobacco. Many methods of administration are disclosed including transdermal administration although there is no example or any further information as to how a composition suitable for transdermal administrations could be prepared. Reference is made to U.S. Pat. No. 5,358,970 to Ruff et al and to the stabilizers disclosed therein. It is stated in each of WO 99/38503, WO 99/38502 and WO99/38504 that these stabilizers may be used to stabilize the bupropion or the bupropion salts. All three of these patent publications exemplify these stabilizers only in combination with bupropion hydrochloride in a form suitable for oral administration.
Bupropion hydrochloride and other bupropion acid addition salts do not cross the dermal barrier by passive diffusion and require a different active mechanism. For facile delivery across the skin into the systemic circulation it is generally required that the bupropion acid addition salts be converted into the base form of the drug and therefore require bases to neutralize the acid. These manipulations would cause complications and could adversely affect the continuous, uninterrupted, and optimal delivery of bupropion from a transdermal system into the systemic circulation.